Non-invasive imaging is a powerful clinical tool for the early diagnosis, and monitoring of various disease processes. Next generation molecular imaging promises unparalleled opportunities for visualizing pulmonary infection and inflammation since molecular and cellular alterations occur earlier in a pathologic process, than structural changes. This rapidly developing technology has become an essential tool in the field of oncology, with similar potential for pulmonary infectious and inflammatory conditions. During phase 1 funding, we developed and validated three novel molecular imaging tracers for evaluating pulmonary diseases with positron emission tomography (PET): 1) 124I-iodo-DPA-713, a synthetic ligand for the translocator protein (TSPO), as a specific imaging biomarker for macrophage-associated pulmonary inflammation, predictive of treatment efficacy and relapse in a Mycobacterium tuberculosis murine infection model; 2) 18F-fluorodeoxysorbitol (18F-FDS), an analog of sorbitol, a Food and Drug Administration (FDA) approved sugar free sweetener, metabolized selectively by Gram-negative bacteria (Enterobacteriaceae), but not mammalian cells, for rapid, specific detection of Gram-negative nosocomial pneumonias and; 3) 11C- Rifampin, a FDA approved first-line TB drug, for rapid, noninvasive multi-compartment pharmacokinetic (PK) assessments. All imaging tracers proposed in this application have been fully validated in preclinical models and have several promising features: a) basis in mechanism with specific cellular targets; b) low molecular weight with suitable PK for lung imaging and; c) high target-to-non-target tissue ratios at convenient times after intravenous injection. Our centra hypothesis is that mechanism-based targeting of pathologic processes by specific PET imaging tracers would provide real-time, early and specific information about pulmonary infections and inflammatory diseases in patients. We propose a multi-disciplinary collaboration, specifically responsive to this RFA (phase 2) to perform initial safety and efficacy testing in human subjects using the FDA Investigational New Drug (IND) or RDRC mechanisms. Our ultimate goal is the bench-to-bedside translation of novel imaging tracers for rapid and noninvasive assessment of pulmonary disease processes and as drug development tools. Imaging tracers developed through this proposal could become valuable clinical tools for pulmonary medicine, and will also be broadly applicable to infectious diseases and other inflammatory conditions. (End of Abstract)